Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated by reference herein as though set forth in full.
Second only to heart disease, cancer is the leading cause of death in the United States, striking one in two men and one in three women (Landis, 1998). Normal tissue homeostasis is a highly regulated process of cell proliferation and cell death. Cancer development is the culmination of complex, multistep biological processes, occurring through the accumulation of genetic alterations resulting in an imbalance in the genes controlling either cell proliferation or cell death. Many if not all of these alterations involve specific cellular growth controlling genes that are mutated. These genes typically are classified as proto-oncogenes and tumor suppressor genes. Any event that leads to alterations of either class of genes leads to abnormal cell growth and can result in cancer.
Proto-oncogenes, upon dysregulation, induce uncontrolled cellular proliferation. Cellular levels of proto-oncogenes are an excellent diagnostic tool to assess the onset of cancer. Moreover, a detailed understanding of proto-oncogenes at a cellular level enables development of strategies for early detection and control of neoplastic tendencies. Upon detection, the dysregulated proto-oncogene can be corrected by various therapies (gene transfer, antibodies, small molecules or others) designed to block the function of the protein.
In vertebrates, proteins modified by gamma-glutamyl carboxylation fall into three major categories: vitamin-K dependent coagulation factors, coregulators of blood coagulation, and osteocalcin and matrix Gla proteins. PRRG4 is a single pass, type I transmembrane protein with a vitamin-K dependent γγ-carboxy-glutamic acid-rich domain (Kulman et al PNAS, 2001). Proline-rich gamma-carboxyglutamic acid protein 2, a paralog of PRRG4 is also widely expressed in many tissues. The function of these proteins is not known, nor are there any reports that suggest a relation to tumor formation.